The Alphavirus genus includes a variety of viruses, all of which are members of the Togaviridae family. The alphavirus genome is a single-stranded, messenger-sense RNA, modified at the 5′-end with a methylated cap, and at the 3′-end with a variable-length poly (A) tract. The viral genome is divided into two regions: the first encodes the nonstructural or replicase proteins (nsP1-nsP4) and the second encodes the viral structural proteins (Strauss and Strauss, (1994) Microbiological Rev. 58:491-562, 494). Structural subunits consisting of a single viral protein, C, associate with themselves and with the RNA genome in an icosahedral nucleocapsid. In the virion, the capsid is surrounded by a lipid envelope covered with a regular array of transmembranal protein spikes, each of which consists trimers of E1 and E2 heterodimers (see Paredes et al., Proc. Natl. Acad. Sci. USA (1993) 90:9095-99; Paredes et al., (1974) Virology 187:324-32; Pedersen et al., (1974) J. Virol. 14:40).
It is well known that live, attenuated viral vaccines are among the most successful means of controlling viral disease. However, for some virus pathogens, immunization with a live virus strain may be either impractical or unsafe. Attenuated, live virus vaccines are recognized as one of the most potent approaches to stimulating a protective immune response to pathogens and have been employed with success in the prevention of infectious diseases. Live virus vaccine vectors utilize the same advantages, stimulating both cytolytic T lymphocyte (CTL) activity and antibody production, without the danger of revertent virulent virus. Venezuelan equine encephalitis virus (VEE) derived vaccine vectors expressing heterologous genes have been developed with success in murine and primate models to protect against challenge with influenza virus (N. L. Davis et al., (1996) J. Virol. 70:3781-7), simian immunodeficiency virus (SIV; N. L. Davis et al., (2000) J. Virology 74:371) and Marburg virus (M. Hevey et al., (1998) Virology 251:2837).
In addition, live virus, non-propagating VEE replicon particles (VRP), expressing heterologous antigens, successfully protect against a lethal challenge of influenza in mice (P. Pushko et al., (1997) Virology 239:389-401) and SIV in primates (N. L. Davis et al., (2000) J. Virology 74:371).
Antibody-dependent enhancement (ADE) is a phenomenon wherein antibodies enhance, rather than inhibit, virus infectivity and pathogenesis. According to the classical theory of ADE, subneutralizing titers of neutralizing anti-viral antibodies form complexes with the virus, which then associate with Fc immunoglobulin and/or complement receptors on macrophages and monocytes. This interaction is believed to result in increased viral infection of these cells (see, e.g., Hawkes et al., (1967) Virology 33:250). In some instances, there is a correlation between ADE and disease, most notably the “dengue shock syndrome” that is associated with infection by dengue viruses (Morens, (1994) Clin. Infectious Diseases 19:500). More recently, it has been proposed that ADE is involved in the pathogenesis of human immunodeficiency virus (HIV) and feline infectious peritonitis virus (FIPV) (see, e.g., Füst, (1997) Parasitology 15 (Suppl): S127; Olsen, (1993) Veterinary Microbiology 36:1).
ADE has been reported in cultured cells in connection with a wide variety of viruses, including flaviviruses, such as Dengue virus, West Nile virus, Murray Valley encephalitis virus, and Yellow fever virus; alphaviruses, such as tick-borne encephalitis virus, Semliki Forest virus, Western equine encephalitis virus, and Sindbis virus; lactate dehydrogenase virus; human respiratory syncytial virus; influenza A virus; rabies virus; feline infectious peritonitis virus (FIPV), human- and feline-immunodeficiency virus (HIV, FIV), and murine cytomegalovirus. (Olsen, (1993) Veterinary Microbiology 36:1; Peiris et al., (1981) J. Gen. Virol. 57:119).
Dendritic cells (DC) are postulated to play important roles in antigen presentation and initiation of several T cell dependent immune responses. DC have been demonstrated to be more potent antigen-presenting cells (APC) than are macrophages or monocytes. Moreover, it has been reported that DC stimulate T cell proliferation up to ten-fold more efficiently than do monocytes (Guyre et al., (1997) Cancer Immunol Immunother. 45:146, 147 col. 2). Accordingly, it would be desirable to target antigens or other therapeutic molecules to DC to produce an enhanced immune response, in particular, to improve the efficacy of vaccines and immunotherapeutic regimes.